Colorectal cancer (CRC) is a major public health problem because it is estimated that 142,820 new cases and 50,830 deaths from CRC in the United States in 2013 (National Cancer Institute website). Early detection and chemical prevention of CRC are two major strategies against it. Moreover, early management of premalignant lesions can significantly reduce CRC-related mortality (Lieberman, Clin Cornerstone 4: 1-10 (2002); Sheehan JAMA, 282: 1254-1257 (1999)). Coxibs (selective cyclooxygenase (COX-2 inhibitors) are the potential chemopreventive agents in the clinical trials because inflammation is associated with the development of CRC (Wang, et al., Nat Rev Cancer 10:181-193 (2010); Wang, et al., Oncogene, 29:781-788 (2010)).
Based on strong data that COX-2 is the major enzyme for the production of inflammatory PGE2 (prostaglandin E2) and PGI2 (prostaglandin 12, also known as prostacylin) and that COX-1 is a key enzyme in the production of cytoprotective PGs (prostaglandins) in the stomach (Funk, et al., J Cardiovasc Pharmacol, 50: 470-479 (2007)), the Food and Drug Administration (FDA) has approved the use of three coxibs, rofecoxib, celecoxib, and valdecoxib. Clinically, nonsteroidal anti-inflammatory drugs (NSAIDs) are the primary choice for the treatment of inflammation (Li, et al., Eur J Pharmacol 681:1-5 (2012)). However, use of conventional NSAIDs is often associated with significant gastrointestinal complications such as ulcers and bleeding. Coxibs were developed to reduce the side effects of NSAIDs (FitzGerald, N Engl J Med 351:1709-1711 (2004)). While substantial evidence from clinical trials (APC, APPROVe, and PreSAP trial) demonstrates that coxibs reduce and prevent the incidence of CRC (Arber, et al., Am J Gastroenterol 106:1135-1146 (2011); Bertagnolli, et al., N Engl J Med 355: 873-884 (2006) and Bresalier, et al., N Engl J Med 352: 1092-1102 (2005)), long-term use of rofecoxib is also associated with an increased risk of side effects, including stroke and cardiovascular events (Bresalier, et al., N Engl J Med 352:1092-1102 (2005)). Consequently, rofecoxib (VIOXX®) and valdecoxib were withdrawn from the market; clinical trials of the use of rofecoxib were stopped in 2004. Currently, celecoxib (CELEBREX®), which is less potent than rofecoxib, is the only coxib on the market. Thus, the current unmet need in this field is to develop a new strategy that can not only enhance the efficacy of coxibs, but also reduce coxib-induced cerebrovascular damage.
It is an object of the present invention to provide compositions and methods which enhance the efficacy of coxibs and reduce coxib-induced cerebrovascular damage or coxib-related side effects.
It is also an object of the present invention to provide compositions and methods of treating cancer with coxibs that have reduced side effects due to coxib treatment.
It is still another object of the invention to provide compositions and methods for treating cancer with combination therapies that reduce the side effects due to coxib treatment.